1. Cannabis Use Measures and Outcomes Assessed in Randomized Controlled Trials for Cannabis Use Disorder
Dustin C. Lee, Ph.D.
Behavioral Pharmacology Research Unit
Johns Hopkins University School of Medicine

2. Introduction Cannabis use disorder (CUD) is prevalent
Cannabis frequently reported as primary substance in treatment admissions
third behind alcohol and opiates
Evidence-based psychosocial treatments developed
relapse rates high
no approved pharmacotherapies
Need for continued focus on improving treatment efficacy

3. Introduction
What are the optimal clinical endpoints for CUD interventions?
Consensus outcomes for tobacco and alcohol
Tobacco – prolonged abstinence
Alcohol – abstinence and reduction in use
elimination of heavy drinking days (i.e. 4/5 drinks per drinking day for females and males)

4. Introduction CUD intervention outcomes
abstinence widely accepted primary outcome
reduction in use might be meaningful alternative
Challenges with measuring cannabis use in clinical trials
evolving cannabis landscape (potency, ROA, concentrates)
no standard “unit” assessment of cannabis quantity
Important to standardize how cannabis use is measured to determine optimal outcome assessments

5. Objectives of Presentation
Primary Purpose: summarize findings from systematic review to provide a platform for in-depth discussion focused on standardizing cannabis use measures and outcomes in CUD trials
Objectives for this presentation
describe approaches for measuring cannabis use in existing randomized controlled trials for CUD
summarize cannabis use outcomes assessed across trials
provide brief overview of other outcome domains assessed in CUD trials

6. Search Strategy
Overall aim was to maximize inclusion of all relevant randomized controlled trials for CUD
Structured literature search in seven electronic databases
PubMed, Embase, Cochrane Central, Cochrane Reviews, Cochrane Other Reviews, CINAHL, and PsycINFO
developed in collaboration with medical librarian
Terms specified population, intervention, and trial design characteristics relevant to CUD interventions
Search included references cited in recent systematic reviews and CUD trials

7. Inclusion Criteria Current cannabis users that were
seeking treatment for CUD and/or
met diagnostic criteria for CUD
Psychosocial and pharmacological interventions for CUD
Trials with any comparison condition
Cannabis use a primary/secondary outcome
Studies were required to be published in English in a peer-reviewed journal

8. Exclusion Criteria Trials examining cannabinoids as therapeutic agents
Interventions not specific to cannabis use
Interventions in ambivalent/non-treatment seekers
Editorials, letters, case studies/series, commentaries, or conference abstracts

9. Study Characteristics
5,877 records identified, 188 full-text documents reviewed
58 randomized controlled trials included in review
36 psychosocial Interventions (PSY)
22 pharmacological Interventions (PHA)
Majority of trials included adult participants
78% included only adults (n=45; 26 PSY, 19 PHA)
15% included only adolescents (n=9; all PSY)
7% included adolescents and adults (n=4, 1 PSY, 3 PHA)

10. Cannabis Use Measures – Self-Report
Self-reported cannabis use assessed in 53 trials
Timeline Followback approach used in 43 trials
Diaries or self-report calendars used in 8 studies
GAIN/ASI used in two trials

11. Cannabis Use Measures – Toxicology
Toxicology testing for THC/metabolites conducted in 46 trials
26 PSY/20 PHA
Reported as a standalone outcome in 22 trials
9 PSY/13 PHA
Used to confirm self-reported abstinence in 19 trials
14 PSY/5 PHA
Both standalone outcome and confirmation of self-reported abstinence in 5 trials
3 PSY/2 PHA

12. Cannabis Use Measures – Toxicology
Urine tests most predominant biological assay
45 trials (11 did not specify details)
5 trials used blood/saliva/hair (4 in addition to urine)
Qualitative “screening” tests used in 23 trials
18 trials used recommended cutoff of 50 ng/mL
4 trials used other cutoffs (100 ng/mL, 20 ng/mL)
multiple cutoffs (20, 50, 100 ng/mL) used in one trial
Quantitative tests (GC/MS, LC/MS/MS) used in 11 trials
to confirm positive tests (6 trials)
only source of toxicology testing (5 trials)

13. Cannabis Use Measures – Toxicology
Concordance between self-reported use and urine toxicology reported in 18 trials
Concordance was high overall
80 to 100% agreement
kappas ranged from 0.6 to 0.9

14. Summary of Cannabis Use Measures
Cannabis use measures fairly consistent across trials
Timeline Followback used in majority of studies
reliability demonstrated for in-person and self-administration via computer/phone
Variability in urine toxicology testing methods
qualitative tests used most frequently
subset of trials used quantitative tests
High concordance between self-report and toxicology

15. Cannabis Use Outcomes

16. Abstinence Outcome Measure Total n (n primary) PSY Trials PHA Trials
% participants w/specific durations of continuous abstinence
19 (13)
12 (8)
7 (5)
Point prevalence abstinence
17 (7)
10 (5)
7 (2)
% negative/positive UA
12 (10)
5 (4)
7 (6)
Longest duration of continuous abstinence
11 (9)
10 (9)
1 (0)
% days abstinent
0 (0)
# days/weeks abstinent
3 (2)
2 (2)
Time to first negative UA
2 (0)
# negative UA
1 (1)
Time to relapse

17. Reduction in Frequency
Outcome Measure
Total
n (n primary)
PSY Trials
PHA Trials
# of days/weeks of cannabis use
26 (16)
18 (14)
8 (2)
% days of cannabis use
15 (6)
8 (5)
7 (1)
# of periods or times per use day
7 (2)
4 (1)
3 (1)
Frequency of cannabis use (categorical)
2 (0)
0 (0)

18. Reduction in Quantity Outcome Measure Total n (n primary) PSY Trials
PHA Trials
Grams
11 (4)
3 (1)
8 (3)
Joints/cones
8 (5)
6 (4)
2 (1)
Standard cannabis units
3 (2)
0 (0)
Total cannabis units (by ROA)
Total money spent
2 (0)
Waterpipes
1 (1)
Inhalations per use day
1 (0)
“Amount” per use day

19. Summary of Cannabis Use Outcomes
Wide range of abstinence and reduction outcomes derived from self-report and toxicology measures
Heterogeneity in time-points used to determine change in use both during and post-TX
Optimal unit of measurement to assess change in quantity not clear
grams, joints most common

20. Other Outcomes – Withdrawal
PHA trials reported withdrawal as an outcome measure
Nine trials used self-report instruments
Marijuana Withdrawal Checklist
Cannabis Withdrawal Scale
Clinical Institute Withdrawal Assessment Scale
Individual symptoms of withdrawal assessed in seven trials
self-report and objective measures of sleep, irritability

21. Measurement Instrument
Other Outcome Domains
Outcome Domain
Total
Trials
PSY
PHA
Measurement Instrument
Presence or Severity of Dependence 21 14 7
SDS
Mood 20 5 15
BDI/BAI
Psychosocial Functioning (Global) 17 3
ASI
Cannabis-related Problems 12
MPS
Readiness to Change/Self-Efficacy 11 10 1
RTC
Alcohol/Other Drug Use 8 6 2
TLFB
Quality of Life 4
WHOQOL-BREF
ASI, Addiction Severity Index; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; MPS, Marijuana Problem Scale; RTC, Readiness to Change Questionnaire; SDS, Severity of Dependence Scale; TLFB, Timeline Followback; WHOQOL-BREF-World Health Organization Quality of Life Assessment

22. Summary of Other Outcome Domains
Secondary outcome domains driven by unique features of a given population/trial
Several domains of interest across trials
e.g. withdrawal, severity of use/dependence, mood, psychosocial functioning, cannabis-related problems, readiness to change/self-efficacy, alcohol and other drug use
No apparent consensus on optimal instruments for each domain

23. Limitations and Considerations
Methodological quality of trials not assessed
Trials evaluating brief interventions in non-dependent/non-treatment seekers excluded
Quantitative comparisons of outcomes not included in review

24. Summary/Discussion Consistency in cannabis use self-report measures
TLFB, urine toxicology included in most studies
Consensus needed on unit of measurement to assess reduction in quantity
is TLFB sufficient or are other measures needed?
Urine toxicology widely-used objective measure
variability in use of qualitative vs. quantitative tests
standardized approach may improve consistency across trials

25. Summary/Discussion
Cannabis use outcomes highly heterogeneous across trials
abstinence and reduction outcomes remain unclear
combining data across existing trials with common features may improve power to detect sensitive outcomes
Wide-range of outcomes reported in other domains
future studies would benefit from a standardized “core” battery of measures in relevant outcome domains

26. Acknowledgements
Thank you to ACTTION for providing the opportunity to conduct this systematic review Specific acknowledgements to co-authors Nicolas Schlienz, Erica Peters, Ryan Vandrey, Eric Strain, Robert Dworkin and Dennis Turk Thank you for your attention!